Cellular signalling最新文献_第9页

tRF-Ser-TGA-011 impedes gastric cancer progression by targeting the MAP3K13/JNK signaling cascade tRF-Ser-TGA-011通过靶向MAP3K13/JNK信号级联抑制胃癌进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-13 DOI: 10.1016/j.cellsig.2025.112323

Yuyan Ma , Hui Lu , Linxin Zhang , Yamei Zhang , Jianjiang Shen , Weiguo Xu , Yanyan Zhang , Feng Yan

Background

Early-stage gastric cancer (GC) is often asymptomatic, leading to frequent late-stage diagnoses. There is a critical need for non-invasive biomarkers to improve early detection and preoperative risk assessment. Although tRNA-derived fragments (tRFs) are increasingly implicated as key modulators in tumorigenesis, their functional significance and mechanistic roles in GC remain poorly understood.

Methods

We conducted high-throughput sequencing to characterize the tRFs' expression profiles between GC tissues and matched tumor-adjacent tissues. The level of tRF-Ser-TGA-011 (tRF-011) was validated via qRT–PCR in cell lines, tissues, and serum. Functional assays—such as CCK-8, colony formation, EdU incorporation, and flow cytometry—were employed to assess its role in proliferation and cell cycle progression. Mechanistic insights were gained through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and western blotting. An in vivo xenograft model was established to evaluate tumor-suppressive effects.

Results

tRF-011 was identified as a pan-cancer diagnostic biomarker with high discriminative capacity. In GC, it distinguished patients from healthy controls with 79.2 % accuracy and stratified clinical stages with 77.4 % accuracy. High tRF-011 expression correlated significantly with improved progression-free survival. Functional experiments revealed that tRF-011 inhibition accelerated proliferation and cell cycle progression, while its overexpression suppressed tumor growth in vivo. Mechanistically, tRF-011 binds AGO2 to assemble a functional RISC complex, directly targeting MAP3K13 mRNA, downregulating JNK signaling, reducing Cyclin D1 expression, and arresting the cell cycle.

Conclusions

Our findings establish tRF-011 as a promising non-invasive biomarker for GC diagnosis and staging, and highlight its therapeutic potential as a tumor suppressor through the AGO2–MAP3K13–JNK–Cyclin D1 axis.

背景：早期胃癌（GC）通常无症状，导致频繁的晚期诊断。迫切需要非侵入性生物标志物来改善早期检测和术前风险评估。尽管trna衍生片段（trf）越来越多地被认为是肿瘤发生的关键调节剂，但它们在GC中的功能意义和机制作用仍然知之甚少。方法：采用高通量测序方法对胃癌组织和匹配的肿瘤邻近组织中tRFs的表达谱进行表征。通过qRT-PCR在细胞系、组织和血清中验证tRF-Ser-TGA-011 （tRF-011）的水平。功能分析——如CCK-8、菌落形成、EdU掺入和流式细胞术——被用来评估其在增殖和细胞周期进程中的作用。通过双荧光素酶报告基因测定、RNA免疫沉淀（RIP）和western blotting获得机制见解。建立了体内异种移植物模型来评估肿瘤抑制作用。结果：tRF-011被鉴定为具有高鉴别能力的泛癌症诊断生物标志物。在GC中，区分患者与健康对照的准确率为79.2% %，区分临床分期的准确率为77.4% %。高tRF-011表达与改善无进展生存期显著相关。功能实验显示，抑制tRF-011可加速细胞增殖和细胞周期进程，而其过表达可抑制体内肿瘤生长。机制上，tRF-011结合AGO2组装功能性RISC复合物，直接靶向MAP3K13 mRNA，下调JNK信号，降低Cyclin D1表达，阻滞细胞周期。结论：我们的研究结果确立了tRF-011作为胃癌诊断和分期的一种有前景的非侵入性生物标志物，并通过AGO2-MAP3K13-JNK-Cyclin D1轴强调了其作为肿瘤抑制因子的治疗潜力。

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引用次数: 0

AKR1B1 bridges metabolic pathways and disease progression AKR1B1连接代谢途径和疾病进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-13 DOI: 10.1016/j.cellsig.2025.112324

Qinyu Zhang , Zhe Cao , Tao Wang , Liyuan Zhong , Zhiliang Sun , Deliang Cao

Aldo-keto reductase 1B1 (AKR1B1) is a highly conserved, NADPH-dependent oxidoreductase that plays pivotal roles across multiple metabolic pathways. Although mounting evidence highlights its diverse contributions to disease progression and its potential as a therapeutic target, the literature remains fragmented with respect to how AKR1B1's metabolic functions intersect with pathogenesis. This review article summarizes the key metabolic functions of AKR1B1 under physiological conditions and discusses its pathological involvement in a spectrum of disorders, including diabetic complications, inflammatory diseases, and cancer. In addition, we review the progress of clinical research on AKR1B1 inhibitors over the past two decades, outlining the achievements and persistent challenges. By integrating insights from metabolism and diseases, this work provides a foundation and inspires new research efforts to advance the understanding of AKR1B1.

Aldo-keto还原酶1B1 （AKR1B1）是一种高度保守的nadph依赖性氧化还原酶，在多种代谢途径中发挥关键作用。尽管越来越多的证据强调了它对疾病进展的不同贡献及其作为治疗靶点的潜力，但关于AKR1B1的代谢功能如何与发病机制交叉的文献仍然是碎片化的。本文综述了AKR1B1在生理条件下的关键代谢功能，并讨论了其在一系列疾病中的病理参与，包括糖尿病并发症、炎症性疾病和癌症。此外，我们回顾了过去二十年来AKR1B1抑制剂的临床研究进展，概述了取得的成就和持续存在的挑战。通过整合代谢和疾病方面的见解，这项工作为推进对AKR1B1的理解提供了基础，并激发了新的研究努力。

引用次数: 0

USP9X promotes acute myeloid leukemia progression and adriamycin resistance by regulating METTL7A deubiquitination USP9X通过调节METTL7A去泛素化促进急性髓性白血病进展和阿霉素耐药。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-13 DOI: 10.1016/j.cellsig.2025.112314

Zhou Yan , Wang Siyi , Wang Siyu , Tan YuanYuan , Li Jiajia

Adriamycin (ADR) resistance remains a significant obstacle in treating acute myeloid leukemia (AML), with most patients eventually developing resistance, resulting in poor prognosis. The deubiquitinase USP9X has been implicated in chemoresistance in AML, while its specific role in ADR resistance remains unclear. Our study proved that the expression levels of USP9X and METTL7A were significantly elevated in HL60/ADR cells. The deficiency of both USP9X and METTL7A obviously inhibited cell growth, as evidenced by decreased colony formation, cell migration, invasion, and proliferation, along with increased cell death. Furthermore, USP9X stabilizes METTL7A stability by regulating its deubiquitination. Notably, up-regulation of METTL7A successfully reversed the growth inhibition caused by USP9X knockdown. These findings were further validated in BALB/c nude mice, where the loss of USP9X and METTL7A reduced tumor growth, and promoted tumor cell apoptosis. Taken together, our findings revealed that USP9X promotes HL60/ADR cell growth in a METTL7A deubiquitination-dependent manner. Therefore, targeting USP9X or METTL7A could provide a promising therapeutic strategy to overcome ADR resistance in AML.

阿霉素（ADR）耐药性仍然是治疗急性髓系白血病（AML）的一个重要障碍，大多数患者最终产生耐药性，导致预后不良。去泛素酶USP9X与AML的化疗耐药有关，但其在ADR耐药中的具体作用尚不清楚。我们的研究证实，USP9X和METTL7A在HL60/ADR细胞中的表达水平显著升高。USP9X和METTL7A缺乏明显抑制细胞生长，表现为集落形成、细胞迁移、侵袭和增殖减少，细胞死亡增加。此外，USP9X通过调节METTL7A的去泛素化来稳定其稳定性。值得注意的是，METTL7A的上调成功地逆转了USP9X敲低引起的生长抑制。这些发现在BALB/c裸鼠中得到进一步验证，USP9X和METTL7A的缺失降低了肿瘤生长，促进了肿瘤细胞凋亡。综上所述，我们的研究结果表明，USP9X以METTL7A去泛素化依赖的方式促进HL60/ADR细胞的生长。因此，靶向USP9X或METTL7A可能为克服AML的ADR耐药提供一种有希望的治疗策略。

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引用次数: 0

STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis sting驱动的TFEB/TFE3激活建立了一个负反馈回路来控制免疫稳态。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-12 DOI: 10.1016/j.cellsig.2025.112322

Yuyuan Wang , Yu Luo , Fei Zhou , Dan Li

Recently several studies have identified that transcription factor EB (TFEB) and transcription factor E3 (TFE3) are the crucial regulators bridging the crosstalk between lysosomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Moreover, this TFEB/TFE3-mediated pathway establishes an essential negative feedback loop, revealing a novel self-regulatory mechanism in innate immunity, which suppresses IRF3 phosphorylation and IFN secretion, reduces caspase-3 activation, and enhances cell survival. Collectively, these findings unveil a critical role for TFEB/TFE3 in the maintenance of immune homeostasis, highlighting their functions in preventing excessive immune responses and protecting cell survival. In this review, we will summarize these findings and discuss the new insights they bring to our understanding of the interplay among the cGAS-STING pathway, lysosomal function, and innate immunity.

近年来的一些研究发现，转录因子EB （TFEB）和转录因子E3 （TFE3）是连接溶酶体和环GMP-AMP合成酶(cGAS)-干扰素基因刺激因子（STING）通路之间串扰的关键调节因子。此外，TFEB/ tfe3介导的这条通路建立了一个必要的负反馈回路，揭示了先天免疫中一种新的自我调节机制，其抑制IRF3磷酸化和IFN分泌，降低caspase-3激活，提高细胞存活率。总之，这些发现揭示了TFEB/TFE3在维持免疫稳态中的关键作用，突出了它们在防止过度免疫反应和保护细胞存活方面的功能。在这篇综述中，我们将总结这些发现，并讨论它们为我们理解cGAS-STING途径、溶酶体功能和先天免疫之间的相互作用带来的新见解。

引用次数: 0

Circadian rhythm: An emerging force for colorectal cancer treatment 昼夜节律：结直肠癌治疗的新兴力量。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-12 DOI: 10.1016/j.cellsig.2025.112321

Jin-jing Zhang , Yu-xi Zhou , Jia-feng Wang , Meng-chuan Wang

The relationship between circadian rhythm disorder and the occurrence and progression of colorectal cancer (CRC) has received attention. The circadian rhythm is maintained by the central clock located in the suprachiasmatic nucleus of the hypothalamus and peripheral oscillators throughout the body. The core clock genes, including CLOCK, BMAL1, PER, and CRY, regulate cell cycle, DNA repair, metabolic homeostasis, and immune surveillance through transcriptional translation feedback loops. In CRC, mutations or expression imbalances in clock genes lead to checkpoint inactivation, attenuated apoptosis, and genomic instability. These disruptions drive tumorigenesis and malignant progression by remodeling the tumor microenvironment (TME). Recent studies revealed circadian-dependent regulation of key oncogenic pathways (mTOR, MAPK/ERK, Wnt/β-catenin) and time-dependent oscillations in immune cell activity, angiogenesis, and metabolic patterns. In clinical practice, chronotherapy strategies based on circadian rhythms have demonstrated enhanced efficacy, radiation sensitivity, and immune responses in preclinical models, with clinical trials validating their potential to improve outcomes while reducing toxicity. In addition, clock gene expression profiles emerge as independent prognostic biomarkers for CRC. Future research needs to integrate multiple omics datasets, and artificial intelligence models can analyze the circadian regulation network in CRC, providing new ideas for the precise prevention and treatment of CRC.

昼夜节律紊乱与结直肠癌（CRC）发生发展的关系已引起人们的关注。昼夜节律由位于下丘脑视交叉上核的中央时钟和遍布全身的外周振荡器维持。核心时钟基因，包括clock、BMAL1、PER和CRY，通过转录翻译反馈回路调节细胞周期、DNA修复、代谢稳态和免疫监视。在结直肠癌中，时钟基因的突变或表达不平衡导致检查点失活、细胞凋亡减弱和基因组不稳定。这些破坏通过重塑肿瘤微环境（TME）驱动肿瘤发生和恶性进展。最近的研究揭示了关键致癌途径（mTOR、MAPK/ERK、Wnt/β-catenin）的昼夜依赖性调节和免疫细胞活性、血管生成和代谢模式的时间依赖性振荡。在临床实践中，基于昼夜节律的时间治疗策略在临床前模型中已经证明了增强的疗效、辐射敏感性和免疫反应，临床试验验证了它们在降低毒性的同时改善结果的潜力。此外，时钟基因表达谱成为结直肠癌的独立预后生物标志物。未来的研究需要整合多个组学数据集，人工智能模型可以分析CRC的昼夜节律调节网络，为CRC的精准防治提供新的思路。

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引用次数: 0

Palmitic acid fuels triple-negative breast cancer through metadherin-dependent fatty acid β-oxidation: Relevance to high fat diet-induced breast cancer progression 棕榈酸通过美粘连依赖性脂肪酸β-氧化促进三阴性乳腺癌：与高脂肪饮食诱导的乳腺癌进展相关

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-12 DOI: 10.1016/j.cellsig.2025.112320

Sunita Kumari , Shashikanta Sahoo , Sriravali Pulipaka , Annatta Thomas , Madhusudana Kuncha , Srigiridhar Kotamraju

Diets rich in saturated fats, specifically palmitic acid (PA), are associated with increased breast cancer risk. However, the exact mechanisms linking dietary fat and cancer progression remain unclear. Herein, we show that PA increases the levels of metadherin (MTDH), an oncogene, and its spliced isoform MTDHΔ7 in triple-negative breast cancer (TNBC) cells. PA significantly increased TNBC cell proliferation and invasiveness in an MTDH-Wt/Δ7-dependent way. Intriguingly, while PA alone promoted mitochondrial fatty acid β-oxidation (FAO), the addition of PA to TNBC cells stably expressing MTDH-Wt/MTDHΔ7 further potentiated FAO and ATP production. Conversely, PA failed to increase FAO in TNBC cells stably depleted of MTDH-Wt/MTDHΔ7. Also, etomoxir, a carnitine palmitoyl transferase (CPT)1 inhibitor, decreased PA- and MTDH-Wt/Δ7-induced TNBC cell invasive potential. Mechanistically, MTDH-Wt/MTDHΔ7-mediated increase in SIRT3 activity led to the activation of CPT1 via its deacetylation, promoting FAO and raising acetyl-CoA levels. Moreover, overexpression of MTDH-Wt/MTDHΔ7 notably increased free fatty acids uptake and subsequent consumption by boosting CD36 levels. Accordingly, depletion of either SIRT3 or CD36 significantly abrogated MTDH-Wt/MTDHΔ7-induced fatty acids uptake and subsequent FAO. Thus, MTDH-Wt/MTDHΔ7 plays a crucial role in utilizing fatty acids to fuel mitochondrial metabolism in TNBC cells. Further, SCID mice bearing sh.MTDH-Wt or sh.MTDHΔ7-MDA-MB-231cells fed a high-fat diet (HFD) showed significant resistance to tumor growth and metastatic spread compared to mice bearing parental MDA-MB-231 cells fed either HFD or chow diet. In conclusion, this study highlights a novel mechanism by which PA or HFD can promote TNBC aggressiveness through MTDH-mediated upregulation of mitochondrial FAO.

富含饱和脂肪的饮食，特别是棕榈酸（PA），与乳腺癌风险增加有关。然而，将饮食脂肪和癌症进展联系起来的确切机制仍不清楚。本研究表明，PA增加了三阴性乳腺癌（TNBC）细胞中致癌基因metadherin （MTDH）及其剪接异构体MTDHΔ7的水平。PA以MTDH-Wt/Δ7-dependent的方式显著增加TNBC细胞的增殖和侵袭性。有趣的是，虽然PA单独促进线粒体脂肪酸β-氧化（FAO），但在稳定表达MTDH-Wt/MTDHΔ7的TNBC细胞中添加PA进一步增强了FAO和ATP的产生。相反，在MTDH-Wt/MTDHΔ7稳定缺失的TNBC细胞中，PA未能增加FAO。此外，依托莫西，一种肉碱棕榈酰转移酶（CPT）1抑制剂，降低了PA-和MTDH-Wt/Δ7-induced TNBC细胞的侵袭潜力。机制上，MTDH-Wt/MTDHΔ7-mediated SIRT3活性的增加通过CPT1的去乙酰化导致CPT1活化，促进FAO和提高乙酰辅酶a水平。此外，MTDH-Wt/MTDHΔ7的过表达通过提高CD36水平显著增加了游离脂肪酸的摄取和随后的消耗。因此，SIRT3或CD36的消耗显著地消除了MTDH-Wt/MTDHΔ7-induced脂肪酸的摄取和随后的FAO。因此，MTDH-Wt/MTDHΔ7在利用脂肪酸促进TNBC细胞线粒体代谢中起着至关重要的作用。此外，与以高脂肪饮食（HFD）喂养母代MDA-MB-231细胞的小鼠相比，以sh.MTDH-Wt或sh.MTDHΔ7-MDA-MB-231cells喂养高脂肪饮食的SCID小鼠对肿瘤生长和转移扩散表现出显著的抵抗力。总之，本研究强调了一种新的机制，即PA或HFD通过mtdh介导的线粒体FAO上调来促进TNBC的侵袭性。

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引用次数: 0

YTHDF3-TRIM2-P53 axis promotes malignant progression in uveal melanoma (UVM) YTHDF3-TRIM2-P53轴促进葡萄膜黑色素瘤（UVM）的恶性进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-12 DOI: 10.1016/j.cellsig.2025.112316

Haoqing Li , Yamin Chen , Wenli Chen , Dongfang Li , Rui Hao , Wei Zhang

Background

Uveal melanoma (UVM) is a rare malignant tumor originating from uveal melanocytes. It accounts for 3 %–5 % of all melanomas and is the most common intraocular malignancy in adults. Advances in the treatment of UVM rely on a deeper understanding of its unique molecular mechanisms.

Methods

Differential and survival analyses assessed YTHDF3 expression and prognosis in UVM. CCK8 and colony formation assays evaluated the impact of YTHDF3 on tumor proliferation. Transwell and wound healing assays examined its effect on tumor migration. GEO data identified potential substrates modified by YTHDF3, while RIP-qPCR confirmed m6A modification. Animal models validated the tumor-promoting role of YTHDF3.

Results

Bioinformatics analysis shows that high expression of YTHDF3 is associated with poor prognosis in UVM. Functional analysis showed that YTHDF3 promoted tumor proliferation, invasion, and migration. RIP-qPCR confirmed that TRIM2 is an m6A modification substrate of YTHDF3. CoIP experiments confirmed the interaction between TRIM2 and P53. Cycloheximide (CHX) pulse-chase assay demonstrated that TRIM2 degraded P53 protein through ubiquitination. Animal models verified that TRIM2 knockdown could inhibit the tumor-promoting effect of YTHDF3.

Conclusion

In this study, our findings show that TRIM2 acts as an m6A-modified substrate of YTHDF3, promoting P53 protein degradation through the ubiquitin-proteasome system. Notably, silencing TRIM2 effectively reduced the tumorigenic effects of YTHDF3 in UVM.

背景：葡萄膜黑色素瘤（UVM）是一种起源于葡萄膜黑色素细胞的罕见恶性肿瘤。它占所有黑色素瘤的3 %-5 %，是成人最常见的眼内恶性肿瘤。UVM治疗的进展依赖于对其独特分子机制的深入了解。方法：通过差异和生存分析评估YTHDF3在UVM中的表达和预后。CCK8和集落形成实验评估了YTHDF3对肿瘤增殖的影响。Transwell和伤口愈合试验检测了其对肿瘤迁移的影响。GEO数据确定了YTHDF3修饰的潜在底物，而RIP-qPCR证实了m6A修饰。动物模型验证了YTHDF3的促肿瘤作用。结果：生物信息学分析显示，YTHDF3高表达与UVM预后不良相关。功能分析显示YTHDF3促进肿瘤增殖、侵袭和迁移。RIP-qPCR证实TRIM2是YTHDF3的m6A修饰底物。CoIP实验证实了TRIM2和P53之间的相互作用。环己亚胺（CHX）脉冲追踪实验表明TRIM2通过泛素化降解P53蛋白。动物模型证实，敲低TRIM2可抑制YTHDF3的促瘤作用。结论：在本研究中，我们的研究结果表明TRIM2作为m6a修饰的YTHDF3底物，通过泛素-蛋白酶体系统促进P53蛋白降解。值得注意的是，沉默TRIM2可有效降低YTHDF3在UVM中的致瘤作用。

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引用次数: 0

CD44-mediated copper accumulation drives Ly6Chi macrophages activation in ulcerative colitis cd44介导的铜积累驱动溃疡性结肠炎中Ly6Chi巨噬细胞的激活

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-11 DOI: 10.1016/j.cellsig.2025.112315

Ying Pei , Xiaoyan Jiang , Lin Xu , Xuefen Huang , Yu Peng , Yuan Zhang , Yifei Xu , Shumin Qin , Shaoju Guo

Ly6C^hi macrophages activation plays a significant role in the progression of inflammation. This study aims to elucidate the role of CD44-mediated copper accumulation in driving Ly6C^hi macrophages activation in ulcerative colitis (UC). We identified Ly6C^hi macrophages and revealed a significant increased proportion in macrophages from scRNA-seq dataset GSE264408. GW2580, which has been validated to effectively suppress the activation of Ly6C^hi macrophages, ameliorated symptoms and pathological features in UC mice. Proteomic analysis revealed elevated CD44 and reduced copper export protein ATP7A expression in the colon of UC mice, with a significant correlation between them. Additionally, copper accumulation was observed in BMDMs-derived Ly6C^hi macrophages. The CD44 monoclonal antibody IM7 substantially reduced copper accumulation, restored ATP7A protein level, decreased ROS level, and suppressed inflammatory activation in Ly6C^hi macrophages. These findings demonstrated that CD44-mediated copper accumulation drives the activation of Ly6C^hi macrophages, representing a critical mechanism in the inflammatory pathogenesis of UC.

Ly6Chi巨噬细胞的活化在炎症的进展中起着重要作用。本研究旨在阐明cd44介导的铜积累在溃疡性结肠炎（UC）中驱动Ly6Chi巨噬细胞活化中的作用。我们鉴定了Ly6Chi巨噬细胞，并从scRNA-seq数据集GSE264408中发现巨噬细胞中Ly6Chi的比例显著增加。GW2580已被证实能有效抑制Ly6Chi巨噬细胞的活化，改善UC小鼠的症状和病理特征。蛋白质组学分析显示，UC小鼠结肠中CD44表达升高，铜输出蛋白ATP7A表达降低，两者之间存在显著相关性。此外，在bmdms衍生的Ly6Chi巨噬细胞中观察到铜积累。CD44单克隆抗体IM7显著减少Ly6Chi巨噬细胞中铜的积累，恢复ATP7A蛋白水平，降低ROS水平，抑制炎症激活。这些发现表明，cd44介导的铜积累驱动Ly6Chi巨噬细胞的激活，是UC炎症发病的关键机制。

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引用次数: 0

Mechanistic insights into L-asparaginase resistance in cancers 癌症中l -天冬酰胺酶耐药性的机理研究

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-11 DOI: 10.1016/j.cellsig.2025.112317

Longfei Deng , Jingjie Zhou , Yujie Liu , Hongjuan Cui

As the most successful example of cancer therapy via amino acid starvation to date, the bacterially derived enzyme L-asparaginase (ASNase) has been used as a key chemotherapeutic agent in the treatment of acute lymphoblastic leukemia (ALL) for more than forty years, which greatly improves the clinical outcome of pediatric and adolescent patients. By degrading L-asparagine (Asn), a non-essential amino acid for normal cells, ASNase induces selective death of some Asn-auxotrophic tumor cells. However, like the inevitable resistance to most chemotherapeutic drugs developed in cancer cells, the resistance to ASNase still emerges, leading to disease relapse and poor prognosis. Moreover, most solid tumors are resistant to ASNase, with the explicit mechanisms not clearly understood, hindering its broad-spectrum application in cancer treatment. Given the lack of a thematic overview of molecular mechanisms of ASNase resistance revealed in recent decade or more, an attempt has been made in this review to outline the current application of ASNase and its resistance as a clinical problem in cancer treatment, and more efforts have been dedicated to emphasizing the summary and discussion of the updated mechanisms of ASNase resistance across different types of human cancers, proposing a complex regulatory network that underpins ASNase resistance.

作为迄今为止通过氨基酸饥饿治疗癌症最成功的例子，细菌来源的l -天冬酰胺酶（ASNase）已经作为治疗急性淋巴细胞白血病（ALL）的关键化疗药物使用了四十多年，极大地改善了儿童和青少年患者的临床预后。ASNase通过降解正常细胞的非必需氨基酸l -天冬酰胺（Asn），诱导一些Asn-营养不良肿瘤细胞选择性死亡。然而，就像癌细胞对大多数化疗药物不可避免的耐药一样，对ASNase的耐药仍然出现，导致疾病复发和预后不良。此外，大多数实体肿瘤对ASNase具有耐药性，其明确的机制尚不清楚，阻碍了其在癌症治疗中的广谱应用。鉴于近十年或更久以来缺乏对ASNase耐药分子机制的专题综述，本文试图概述ASNase的当前应用及其耐药作为癌症治疗的临床问题，并致力于强调总结和讨论不同类型人类癌症中ASNase耐药的最新机制。提出了一个支持ASNase抗性的复杂监管网络。

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引用次数: 0

Trps1 enhances Hdac4 and Gli3 protein stability and nuclear localization independent of PKA and PP2A signaling Trps1增强Hdac4和Gli3蛋白的稳定性和核定位，不依赖于PKA和PP2A信号。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-11 DOI: 10.1016/j.cellsig.2025.112301

Manuela Wuelling , Lara M. Janz , Anja B. Ende , Nina Schulze , Andrea Vortkamp

The growth of endochondral bones relies on the coordinated proliferation and hypertrophy of chondrocytes. This process is governed by several transcription factors and epigenetic modifiers that regulate distinct steps, likely by assembling into larger complexes that bind to DNA. The transcription factor Trps1 has previously been shown to interact with the activator form of Gli3 (Gli3A) and the histone deacetylase Hdac4, two critical regulators of chondrocytes proliferation and differentiation. Here, we show that the interaction with Trps1 increases the abundance of both proteins and promotes their nuclear localization. We further demonstrate that Trps1 acts independently of PKA and PP2A activity, which have been reported to regulate the nuclear localization and activity of Gli3A and Hdac4. Trps1 and Gli3A complexes were predominantly found in proliferating chondrocytes, whereas Trps1 and Hdac4 interactions occurred more frequently in prehypertrophic chondrocytes, suggesting differentiation-specific changes in protein interactions. These findings reveal the regulation of protein abundance and nuclear availability as a novel mechanism by which Trps1 controls gene expression during chondrocyte differentiation.

软骨内骨的生长依赖于软骨细胞的协调增殖和肥大。这个过程是由几个转录因子和表观遗传修饰因子控制的，这些转录因子和表观遗传修饰因子调节不同的步骤，可能通过组装成更大的结合DNA的复合物。转录因子Trps1先前已被证明与Gli3的激活因子形式（Gli3A）和组蛋白去乙酰化酶Hdac4相互作用，这是软骨细胞增殖和分化的两个关键调节因子。在这里，我们发现与Trps1的相互作用增加了这两种蛋白的丰度，并促进了它们的核定位。我们进一步证明Trps1独立于PKA和PP2A活性起作用，而PKA和PP2A已被报道调节Gli3A和Hdac4的核定位和活性。Trps1和Gli3A复合物主要存在于增殖软骨细胞中，而Trps1和Hdac4相互作用更频繁地发生在肥大前软骨细胞中，提示蛋白质相互作用的分化特异性变化。这些发现揭示了Trps1在软骨细胞分化过程中调控蛋白丰度和核可用性的新机制。

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引用次数: 0